The present invention relates to an industrially advantageous production method for forming a carbon-carbon bond at the 5-position of oxazole.
There are various production methods (e.g. WO97/36882) of compounds having a carbon substituent (a group bonded via a carbon) bonded at the 5-position of oxazole. Most of them require introduction of a necessary carbon substituent before constructing an oxazole ring. However, the starting material usable for the production method is limited and the synthesis thereof is associated with difficulty.
In view of the above, the development of an easy and simple method for introducing a carbon substituent into the 5-position of oxazole is highly significant, and finding of a reaction permitting direct formation of a carbon-carbon bond on an oxazole having no substituent at the 5-position is extremely significant.
The present inventors have conducted intensive studies in an attempt to introduce a carbon substituent into the 5-position of oxazole and found for the first time that a reaction of an oxazole having no substituent at the 5-position (particularly one having an oxo group or amino group at the 2-position) with olefin in the presence of an acid or base unexpectedly results in an easy reaction with the olefin and the formation of a carbon-carbon bond at the 5-position of the oxazole, based on which they investigated further and completed the present invention.
Accordingly, the present invention relates to:
(1) a method of producing a compound represented by the formula 
xe2x80x83wherein
R1 and R2 are each a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
R3 is an electron-withdrawing group, and
R4, R5 and R6 are each a hydrogen atom or an optionally substituted hydrocarbon group, or a salt thereof, which method comprises reacting a compound represented by the formula 
xe2x80x83wherein the symbols in the formula are as defined above, or a salt thereof, with a compound represented by the formula 
xe2x80x83wherein the symbols in the formula are as defined above, or a salt thereof, in the presence of an acid or a base;
(2) the production method of the aforementioned (1), wherein R1 and R2 are each a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
(3) the production method of the aforementioned (1), wherein R1 is an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group;
(4) the production method of the aforementioned (1), wherein R1 is an optionally substituted phenyl group;
(5) the production method of the aforementioned (1), wherein R2 is a hydrogen atom;
(6) the production method of the aforementioned (1), wherein R4, R5 and R6 are each a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group;
(7) the production method of the aforementioned (1), wherein R4, R5 and R6 are each a hydrogen atom;
(8) the production method of the aforementioned (1), wherein R3 is xe2x80x94CN, xe2x80x94COOR7 (R7 is a hydrogen atom or an optionally substituted hydrocarbon group) or xe2x80x94COR8 (R8 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group);
(9) the production method of the aforementioned (1), wherein R3 is xe2x80x94CN;
(10) the production method of the aforementioned (1), wherein R3 is xe2x80x94COOR7 (R7 is a hydrogen atom or an optionally substituted alkyl group);
(11) the production method of the aforementioned (1), wherein R3 is xe2x80x94COR8 (R8 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group);
(12) the production method of the aforementioned (1), wherein the reaction is carried out in the presence of an acid;
(13) a method of producing a compound represented by the formula 
xe2x80x83wherein
R1 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
R18 is an optionally substituted amino group, and other symbols are as defined above, or a salt thereof, which method comprises reacting a compound represented by the formula 
xe2x80x83wherein the symbols in the formula are as defined above, or a salt thereof, with a compound represented by the formula (II) or a salt thereof, in the presence of an acid;
(14) a method of producing a compound represented by the formula 
xe2x80x83wherein
R1 is as defined above,
R4, R5, R6 are each a hydrogen atom or an optionally substituted hydrocarbon group,
R19 is an optionally substituted heterocyclic group containing nitrogen, which is bonded via a nitrogen atom, and
R20 is an optionally substituted hydrocarbon group, or a salt thereof, which method comprises reacting a compound represented by the formula (I) or a salt thereof with a compound represented by the formula 
xe2x80x83wherein R7 is a hydrogen atom or an optionally substituted hydrocarbon group, and other symbols are as defined above, or a salt thereof, in the presence of an acid or a base to give a compound represented by the formula 
xe2x80x83wherein the symbols in the formula are as defined above, or a salt thereof, subjecting this compound to halogenation reaction to give a compound represented by the formula 
xe2x80x83wherein X is a halogen atom, and other symbols are as defined above, or a salt thereof, reacting this compound with a compound represented by the formula: R19xe2x80x94H (XII) [R19 is as defined above] to give a compound represented by the formula 
xe2x80x83wherein the symbols in the formula are as defined above, or a salt thereof, subjecting this compound to a reduction reaction to give a compound represented by the formula 
xe2x80x83wherein the symbols in the formula are as defined above, or a salt thereof, reacting this compound with a compound represented by the formula: R10SO2Cl (XV) [R10 is an optionally substituted alkyl group or an optionally substituted aryl group] or a halogenating agent to give a compound represented by the formula 
xe2x80x83wherein Za is a halogen atom or xe2x80x94OSO2R10 (R10 is as defined above), and other symbols are as defined above, or a salt thereof, and reacting this compound with a compound represented by the formula: R20xe2x80x94OH (XVII) [R20 is as defined above];
(15) a method of producing a compound represented by the formula (XVIII) or a salt thereof, which comprises reacting a compound represented by the formula (IX) or a salt thereof with a compound represented by the formula (IIa) or a salt thereof in the presence of an acid to give a compound represented by the formula 
xe2x80x83wherein the symbols in the formula are as defined above, or a salt thereof, subjecting this compound to halogenation reaction to give a compound represented by the formula (XIa) or a salt thereof, reacting this compound with a compound represented by the formula (XII) to give a compound represented by the formula (XIII) or a salt thereof, subjecting this compound to a reduction reaction to give a compound represented by the formula (XIV) or a salt thereof, reacting this compound with a compound represented by the formula (XV) or halogenating agent to give a compound represented by the formula (XVI) or a salt thereof, and reacting this compound with a compound represented by the formula (XVII);
(16) methyl. 4-(4-chlorophenyl)-2-(2-methylimidazol-1-yl)-5-oxazolepropionate; and the like.
The xe2x80x9chydrocarbon groupxe2x80x9d of the above-mentioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1, R2, R4, R5, R6, R7 or R8 is exemplified by aliphatic hydrocarbon group, alicyclic hydrocarbon group, aryl group, aralkyl group and the like.
Examples of the aliphatic hydrocarbon group include linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atom(s), such as alkyl group, alkenyl group, alkynyl group and the like, with preference given to alkyl group.
Preferable examples of alkyl group include alkyl group having 1 to 10 carbon atom(s) (preferably alkyl group having 1 to 6 carbon atom(s)), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
Preferable examples of alkenyl group include alkenyl group having 2 to 10 carbon atoms, such as vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like.
Preferable examples of alkynyl group include alkynyl group having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
The above-mentioned aliphatic hydrocarbon group may have the same or different, 1 to 5, preferably 1 to 3, substituent(s) at substitutable position(s). Examples of the substituent include (i) halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), (ii) C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like), (iii) hydroxy group, (iv) amino group, (v) mono- or di-C1-6 alkylamino group (e.g., methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino and the like), (vi) nitro group, (vii) carboxyl group, (viii) C1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like), (ix) C1-6 alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like), (x) benzoyl group, (xi) phenyl group, (xii) phenoxy group, (xiii) benzyloxy group and the like.
Examples of the alicyclic hydrocarbon group include saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as cycloalkyl group, cycloalkenyl group, cycloalkadienyl group and the like (preferably cycloalkyl group).
Preferable examples of cycloalkyl group include cycloalkyl group having 3 to 10 carbon atoms (preferably cycloalkyl group having 3 to 8 carbon atoms), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl and the like.
Preferable examples of cycloalkenyl group include cycloalkenyl group having 3 to 10 carbon atoms, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.
Preferable examples of cycloalkadienyl group include cycloalkadienyl group having 4 to 10 carbon atoms, such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.
The above-mentioned alicyclic hydrocarbon group may have the same or different, 1 to 5, preferably 1 to 3, substituent(s) at substitutable position(s). Examples of the substituent include (i) halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), (ii) C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like), (iii) hydroxy group, (iv) amino group, (v) mono- or di-C1-6 alkylamino group (e.g., methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino and the like), (vi) nitro group, (vii) carboxyl group, (viii) C1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like), (ix) C1-6 alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like), (x) benzoyl group, (xi) phenyl group, (xii) phenoxy group, (xiii) benzyloxy group and the like.
The aryl group is exemplified by aryl group having 6 to 14 carbon atoms, such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
The aralkyl group is exemplified by C6-14 aryl-C1-6 alkyl group, such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,-l-naphthylmethyl, 2-naphthylmethyl and the like. Of these, phenyl-C1-4 alkyl group and the like are preferable.
The above-mentioned aryl group and aralkyl group may have the same or different, 1 to 5, preferably 1 to 3 substituent(s) at substitutable position(s). Examples of the substituent include (i) C1-3 alkylenedioxy group (e.g., methylenedioxy, ethylenedioxy and the like), (ii) nitro group, (iii) cyano group, (iv) carboxyl group, (v) C1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like), (vi) hydroxy group, (vii) halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), (viii) optionally halogenated C1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl and the like), (ix) C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like), (x) benzyloxy group, (xi) phenyl group, (xii) benzoyl group, (xiii) phenoxy group, (xiv) amino group, (xv) mono- or di-C1-6 alkylamino group (e.g., methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino and the like), (xvi) C1-6 alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like) and the like.
The xe2x80x9cheterocyclic groupxe2x80x9d of the above-mentioned xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1, R2 or R8 is exemplified by 5 to 10-membered aromatic heterocyclic groups such as pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl etc.), pyrimidinyl (e.g., 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl etc.), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl etc.), pyrazinyl (e.g., 2-pyrazinyl etc.), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl etc.), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl etc.), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl etc.), isoxazolyl, isothiazolyl, thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl etc.), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl etc.), 1,2,4-oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl etc.), 1,2,4-triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl etc.), 1,2,3-triazolyl (e.g., 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl etc.), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl etc.), benzimidazolyl (e.g., benzimidazol-1-yl, benzimidazol-2-yl etc.), indolyl(e.g., indol-1-yl, indol-3-yl etc.), 1H-indazolyl (e.g., 1H-indazol-1-yl etc.), 1H-pyrrolo[2,3-b]pyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-1-yl etc.), 1H-pyrrolo[2,3-b]pyridyl (e.g., 1H-pyrrolo[2,3-b]pyridin-1-yl etc.), 1H-imidazo[4,5-b]pyridyl (e.g., 1H-imidazo[4,5-b]pyridin-1-yl etc.), 1H-imidazo[4,5-c]pyridyl (e.g., 1H-imidazo[4,5-c]pyridin-1-yl etc.), 1H-imidazo[4,5-b]pyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-1-yl etc.) and the like; 5 to 7-membered non-aromatic heterocyclic groups such as pyrrolidinyl (e.g., 1-pyrrolidinyl etc.), piperidyl (e.g., 1-piperidyl etc.), morpholinyl (e.g., morpholin-4-yl etc.), thiomorpholinyl (e.g., thiomorpholin-4-yl etc.), piperazinyl (e.g., 1-piperazinyl etc.), hexametbyleneiminyl (e.g., hexamethylenimin-1-yl etc.), oxazolidinyl (e.g., oxazolidin-3-yl et.), thiazolidinyl (e.g., thiazolidin-3-yl, thiazolidin-2-yl etc.), imidazolidinyl (e.g., imidazolidin-3-yl etc.), imidazolinyl (e.g., imidazolin-1-yl, imidazolin-2-yl etc.), oxazolinyl (e.g., oxazolin-2-yl etc.), thiazolinyl (e.g., thiazolin-2-yl etc.), oxazinyl (e.g., oxazin-2-yl etc.) and the like, and the like. Of these, an aromatic heterocyclic group is preferable, and furyl, thienyl, pyridyl, quinolyl, isoquinolyl and the like are particularly preferably used.
The above-mentioned heterocyclic group may have the same or different, 1 to 5, preferably 1 to 3, substituent(s) at substitutable position(s). Examples of the substituent include (i) nitro group, (ii) cyano group, (iii) carboxyl group, (iv) C1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like), (v) hydroxy group, (vi) halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), (vii) optionally halogenated C1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl and the like), (viii) C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like), (ix) benzyloxy group, (x) phenyl group, (xi) benzoyl group, (xii) phenoxy group, (xiii) amino group, (xiv) mono- or di-C1-6 alkylamino group (e.g., methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino and the like), (xv) C1-6 alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like), and the like.
The benzyloxy group, benzoyl group, phenyl group and phenoxy group as a substituent of the above-mentioned xe2x80x9chydrocarbon groupxe2x80x9d and xe2x80x9cheterocyclic groupxe2x80x9d may have the same or different, 1 to 5, preferably 1 to 3, substituent(s) at substitutable position(s). Examples of the substituent include (i) C1-3 alkylenedioxy group (e.g., methylenedioxy, ethylenedioxy and the like), (ii) nitro group, (iii) cyano group, (iv) hydroxy group, (v) halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), (vi) C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like), (vii) C1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like), (viii) benzyloxy group, (ix) amino group, (x) mono- or di-C1-6 alkylamino group (e.g., methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino and the like) and the like.
The above-mentioned electron-withdrawing group represented by R3 is exemplified by xe2x80x94CN, xe2x80x94COOR7 (R7 is hydrogen atom or optionally substituted hydrocarbon group), xe2x80x94COR8 (R8 is hydrogen atom, optionally substituted hydrocarbon group or optionally substituted heterocyclic group) and the like, as well as optionally amidated carboxyl group, nitro group, a group represented by xe2x80x94(SOm)R15 (wherein m is 1 or 2 and R15 is optionally substituted hydrocarbon group), a group represented by xe2x80x94PR11R12 (wherein R11 and R12 are each optionally substituted hydrocarbon group), a group represented by xe2x80x94(PO)(OR13)(OR14) wherein R13 and R14 are each hydrogen atom or optionally substituted hydrocarbon group) and the like. Of these, xe2x80x94CN, xe2x80x94COOR7 (R7 is hydrogen atom or optionally substituted hydrocarbon group), xe2x80x94COR8 (R8 is hydrogen atom, optionally substituted hydrocarbon group or optionally substituted heterocyclic group) and the like are preferable.
As the aforementioned xe2x80x9camidated carboxyl groupxe2x80x9d as an xe2x80x9celectron-withdrawing groupxe2x80x9d, there are exemplified a group represented by xe2x80x94(CO)NR16R17 wherein R16 and R17 are each hydrogen or optionally substituted hydrocarbon group, and R16 and R17 may be bonded with each other to form, together with the adjacent nitrogen atom, 5 to 7-membered, preferably 5 or 6-membered, cyclic amino (e.g., tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine and the like) and the like.
The aforementioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R11, R12, R13, R14, R15, R16 or R17 is exemplified by those exemplified as the aforementioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1.
In the group represented by the formula xe2x80x94PR11R12 or xe2x80x94(PO)(OR13)(OR14) as the aforementioned xe2x80x9celectron-withdrawing groupxe2x80x9d, R11 and R12 or R13 and R14 may be bonded with each other to form, for example, lower (C2-6)alkylene (e.g., dimethylene, trimethylene, tetramethylene and the like), lower (C2-6)alkenylene (e.g., xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 and the like) and the like, preferably lower (C1-6)alkylene, more preferably lower (C2-4)alkylene. These divalent groups may have substituent(s), where examples of the substituent include hydroxyl group, halogen, C1-4 alkyl, C1-4 alkoxy and the like.
In the above-mentioned formulas, R1 and R2 are preferably hydrogen atom, optionally substituted alkyl group, optionally substituted aralkyl group, optionally substituted aryl group, optionally substituted heterocyclic group and the like. Particularly, R1 is preferably optionally substituted aryl group or optionally substituted aromatic heterocyclic group, particularly, R1 is preferably optionally substituted phenyl group. R1 is more preferably phenyl group optionally having 1 to 3 substituent(s) selected from halogen atom (preferably chlorine), optionally halogenated C1-6 alkyl group (preferably trifluoromethyl) or C1-6 alkoxy group (preferably methoxy). Particularly preferably, R1 is phenyl group optionally substituted by 1 to 3 halogen atom(s) (preferably chlorine). As R2, hydrogen atom is preferable.
In the above-mentioned formulas, R4, R5 and R6 are preferably hydrogen atom, optionally substituted alkyl group (preferably C1-6 alkyl group such as methyl and the like), optionally substituted aryl group (preferably phenyl) and the like, particularly preferably hydrogen atom.
In the above-mentioned formulas, R3 is preferably xe2x80x94CN, xe2x80x94COOR7 (R7 is hydrogen atom or optionally substituted alkyl group) or xe2x80x94COR8 (R8 is hydrogen atom, optionally substituted alkyl group or optionally substituted aryl group), particularly xe2x80x94COOR7 (R7 is hydrogen atom or optionally substituted alkyl group).
As used herein, R7 and R8 are particularly preferably C1-6 alkyl group such as methyl and the like.
With regard to the above-mentioned xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R18, the if substituent is exemplified by the aforementioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d exemplified as R1 and the like. R18 is preferably amino group optionally mono- or di-substituted by substituent(s) selected from C1-6 alkyl group and C6-14 aryl-C1-6 alkyl group. R18 is more preferably amino group.
In the present invention, the aforementioned compound represented by the formula (I) or a salt thereof [hereinafter sometimes to be referred to as compound (I)] is reacted with the aforementioned compound represented by the formula (II) or a salt thereof [hereinafter sometimes to be referred to as compound (II)], in the presence of an acid or a base to produce a compound represented by the aforementioned formula (III) or a salt thereof [hereinafter sometimes to be referred to as compound (III)].
In the present specification, compound (II) and compound (III), wherein R3 is xe2x80x94COOR7 (R7 is as defined above), may be described as compound (IIa) and compound (IIIa), respectively.
Examples of the acid to be used in this reaction include mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid etc.), organic acids (e.g., acetic acid, propionic acid, butyric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid etc.), Lewis acids (e.g., aluminum chloride, tin chloride, iron chloride, titanium chloride (titanium tetrachloride), boron trifluoride, boron trichloride etc.), strong acid resin (e.g., Dowex 50, Amberlite IR120 etc.), polyphosphoric acid, polyphosphoric acid ester and the like. The acid is preferably sulfuric acid, methanesulfonic acid or boron trifluoride. Of these, mineral acids are preferable, particularly, sulfuric acid is preferable.
Examples of the base to be used in this reaction include alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium-tert-butoxide, potassium-tert-butoxide etc.), tertiary amines (e.g., trimethylamine, triethylamine, tributylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) etc.), aromatic amines (e.g., pyridine, picoline, quinoline, dimethylaniline, diethylaniline etc.), strong base resins (e.g., Dowex 1, Amberlite IRA400, BioRad AGI etc.) and the like. The base is preferably alkali metal alkoxides or tertiary amines, particularly preferably sodium methoxide or triethylamine.
This reaction is generally carried out in a solvent. Examples of the solvent include halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene etc.), ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), nitrites (e.g., acetonitrile, propionitrile and the like), esters (methyl acetate, ethyl acetate etc.), alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, methoxyethanol etc.) and the like. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio. Alternatively, the aforementioned acid or base may be used as a solvent. The solvent is preferably nitrile, alcohol, aromatic hydrocarbon, more preferably, acetonitrile, methanol or toluene. Particularly, acetonitrile is preferable.
The amount of compound (II) to be used is generally 1-20 equivalent(s), preferably 1-5 equivalent(s), relative to compound (I). The amount of the acid or base to be used is generally 0.01-30 equivalent(s), preferably 0.05-10 equivalents), relative to compound (I).
The reaction of compound (I) and compound (II) is preferably carried out in the presence of an acid, wherein the amount of the acid to be used is generally 0.1-30 equivalent(s), preferably 0.5-10 equivalent(s), relative to compound (I).
The reaction temperature is generally xe2x88x9230xc2x0 C. to 150xc2x0 C., preferably xe2x88x9210xc2x0 C. to 100xc2x0 C.
The reaction time is generally 0.5 hour to 24 hours, preferably 1 hour to 10 hours.
The compound (III) thus obtained can be easily isolated by a known method, such as concentration, changing of liquid properties, solvent extraction, crystallization and the like. Recrystallization affords a compound having a higher purity.
In the production method of the present invention, compound (I) as a starting material can be produced, for example, according to the following method. 
wherein M is an alkali metal such as sodium, potassium and the like, Z is a halogen atom (e.g., chlorine, bromine and the like), Y is a halogen atom (e.g., chlorine, bromine and the like) or xe2x80x94OSO2R10 (R10 is an optionally substituted alkyl group or an optionally substituted aryl group), Ac is an acetyl group, R9 is an alkyl group, aralkyl group or aryl group, and other symbols are as defined above.
In the above-mentioned formula, examples of the xe2x80x9calkyl groupxe2x80x9d represented by R9 include the aforementioned xe2x80x9calkyl group (preferably alkyl group having 1 to 6 carbon atom(s))xe2x80x9d exemplified for R1.
In the above-mentioned formula, examples of the xe2x80x9caralkyl groupxe2x80x9d represented by R9 include the aforementioned xe2x80x9caralkyl group (preferably C6-14 aryl-C1-6 alkyl group)xe2x80x9d exemplified for R1.
In the above-mentioned formula, examples of the xe2x80x9caryl groupxe2x80x9d represented by R9 include the aforementioned xe2x80x9caryl group (preferably aryl group having 6 to 14 carbon atoms)xe2x80x9d exemplified for R1.
In the above-mentioned formula, examples of the xe2x80x9calkyl groupxe2x80x9d of the xe2x80x9coptionally substituted alkyl groupxe2x80x9d represented by R10 include the aforementioned xe2x80x9calkyl group (preferably alkyl group having 1 to 6 carbon atom(s))xe2x80x9d exemplified for R1. The xe2x80x9calkyl groupxe2x80x9d may have the same or different, 1 to 5, preferably 1 to 3, substituent(s) at substitutable position(s) Examples of such substituent include those similar to the substituent of the aforementioned xe2x80x9caliphatic hydrocarbon groupxe2x80x9d exemplified for R1.
In the above-mentioned formula, the xe2x80x9caryl groupxe2x80x9d of the xe2x80x9coptionally substituted aryl groupxe2x80x9d represented by R10 includes the aforementioned xe2x80x9caryl group (preferably aryl group having 6 to 14 carbon atoms)xe2x80x9d exemplified for R1. The xe2x80x9caryl groupxe2x80x9d may have the same or different, 1 to 5, preferably 1 to 3, substituent(s) at substitutable position(s). Examples of such substituent include those similar to the substituent of the aforementioned xe2x80x9caryl groupxe2x80x9d exemplified as R1.
R10 is particularly preferably C1-6 alkyl group (preferably methyl); a phenyl group optionally substituted by 1 to 3 C1-6 alkyl group(s) (preferably methyl).
First, compound (IV) and compound (V) are reacted in the presence of an acid to give compound (VI). This reaction is generally carried out in a solvent. Examples of the solvent include alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, methoxyethanol and the like), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene and the like), ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), nitriles (e.g., acetonitrile, propionitrile and the like), esters (methyl acetate, ethyl acetate and the like) and the like. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio. The solvent is particularly preferably alcohol such as isopropanol and the like.
As the acid, for example, organic acids (e.g., acetic acid, propionic acid, butyric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and the like), mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like) and the like are used. Of these, organic acids are preferable, and acetic acid is particularly preferable.
The amount of compound (V) to be used is generally 1-10 equivalent(s), preferably 1-5 equivalents), relative to compound (IV). The amount of acid to be used is generally 1-30 equivalent(s), preferably 1-10 equivalents), relative to compound (V).
The reaction temperature is generally xe2x88x9210xc2x0 C. to 120xc2x0 C., preferably xe2x88x925xc2x0 C. to 90xc2x0 C.
The reaction time is generally 0.5 hour to 72 hours, preferably 1 hour to 36 hours.
The compound (VI) can be also produced by reacting compound (IV) with compound (VII) in the presence of a base to give compound (VIII), and reacting the compound (VIII) with ammonium acetate.
The reaction of compound (IV) and compound (VII) is generally carried out in a solvent in the presence of a base. This solvent may be any as long as it does not inhibit the reaction and is exemplified by halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene and the like), ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), nitrites (e.g., acetonitrile, propionitrile and the like), esters (methyl acetate, ethyl acetate and the like), dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio.
As the base, for example, tertiary amines (e.g., trimethylamine, triethylamine, tributylamine, N-ethyldiisopropylamine, N-methylmorpholine and the like), aromatic amines (e.g., pyridine, picoline, quinoline and the like), alkali metal carbonate (e.g., sodium hydrogencarbonate, potassium carbonate, sodium carbonate, cesium carbonate and the like), alkali metal hydroxide (e.g., potassium hydroxide, sodium hydroxide, calcium hydroxide and the like) and the like are used.
Each amount of compound (VII) and a base to be used is generally 1-5 equivalent(s), preferably 1-3 equivalent(s), relative to compound (IV).
The reaction temperature is generally xe2x88x9230xc2x0 C. to 100xc2x0 C., preferably xe2x88x9215xc2x0 C. to 60xc2x0 C.
The reaction time is generally 15 minutes to 24 hours, preferably 0.5 hour to 12 hours.
The thus-obtained compound (VIII), after isolation by a known method or as its reaction mixture, is reacted with ammonium acetate to give compound (VI). This reaction is carried out in a solvent. This solvent may be any as long as it does not inhibit the reaction and is exemplified by halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene and the like), ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), nitrites (e.g., acetonitrile, propionitrile and the like), esters (methyl acetate, ethyl acetate and the like), dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio. A weak acid may be used as a solvent. The weak acid to be used includes, for example, formic acid, acetic acid, propionic acid and the like. A mixed solvent of these weak acids and the above-mentioned solvents may be used for the reaction.
The amount of ammonium acetate to be used is generally 1-20 equivalents), preferably 1-10 equivalent(s), relative to compound (VIII).
The reaction temperature is generally xe2x88x9210xc2x0 C. to 150xc2x0 C., preferably 0xc2x0 C. to 120xc2x0 C.
The reaction time is generally 15 minutes to 24 hours, preferably 0.5 hour to 12 hours.
The thus-obtained compound (VI), after isolation by a known method or as its reaction mixture, is used as the starting material for the production method of the present invention, as well as the starting material for producing compound (I) by N-alkylation in the presence of a base. The conditions of the N-alkylation reaction may be those under which compound (VIII) is produced or similar method. As the base, those exemplified for the reaction below of the compound (IV) with cyanamide compound are used.
According to the present invention, the aforementioned compound represented by the formula (IX) or a salt thereof [hereinafter sometimes to be referred to as compound (IX)] and compound (II) are reacted in the presence of an acid to give a compound represented by the aforementioned formula (X) or a salt thereof [hereinafter sometimes to be referred to as compound (X)].
In the present specification, compound (X) wherein R3 is xe2x80x94COOR7 (R7 is as defined above) may be referred to as compound (Xa).
As the acid to be used for this reaction, those exemplified for the aforementioned reaction of compound (I) and compound (II) are mentioned. Of these, Lewis acids are preferable, particularly titanium chloride is preferable.
This reaction is generally carried out in a solvent. Examples of the solvent include those exemplified for the aforementioned reaction of compound (I) and compound (II). In some cases, the acid to be used may be used as a solvent. The solvent is preferably halogenated hydrocarbon, particularly preferably dichloromethane.
The amount of compound (II) to be used is generally 1-20 equivalent(s), preferably 1-5 equivalents), relative to compound (IX). The amount of the acid to be used is generally 0.1-30 equivalents), preferably 0.5-10 equivalent(s), relative to compound (IX).
The reaction temperature and reaction time are the same as those for the aforementioned reaction of compound (I) and compound (II).
The compound (X) thus obtained can be easily isolated by a known method such as concentration, changing of liquid properties, solvent extraction, crystallization and the like. Recrystallization affords a compound having a higher purity.
The compound (IX) to be used as a starting material in the above-mentioned production method can be produced, for example, by reacting compound (IV) with a cyanamide compound represented by the formula: R18CN [the symbol in the formula is as defined above] in the presence of a base.
As the base, for example, tertiary amines (e.g., trimethylamine, triethylamine, tributylamine, N-ethyldiisopropylamine, N-methylmorpholine and the like), aromatic amines (e.g., pyridine, picoline, quinoline, isoquinoline, N,N-dimethylaniline, N,N-diethylaniline and the like), alkali metal carbonates (e.g., sodium hydrogencarbonate, potassium carbonate, sodium carbonate, cesium carbonate and the like), alkali metal hydroxides (e.g., potassium hydroxide, sodium hydroxide, calcium hydroxide and the like), alkali metal alkoxides (e.g., potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium n-butoxide, sodium tert-butoxide and the like) and the like are used. Particularly, alkali metal alkoxide is preferable.
This reaction is generally carried out in a solvent. This solvent may be any as long as it does not inhibit the reaction and is exemplified by alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, methoxyethanol and the like), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene, benzotrifluoride and the like), ethers (e.g. ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), nitriles (e.g., acetonitrile, propionitrile and the like), esters (methyl acetate, ethyl acetate and the like) and the like. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio. The solvent is preferably alcohol.
The amount of the cyanamide compound to be used is generally 1-10 equivalent(s), preferably 1-5 equivalents), relative to compound (IV).
The amount of the base to be used is generally 0.01-10 equivalents), preferably 0.1-5 equivalents), relative to compound (IV).
The reaction temperature is generally xe2x88x9250xc2x0 C. to 150xc2x0 C., preferably xe2x88x9220xc2x0 C. to 120xc2x0 C.
The reaction time is generally 15 minutes to 24 hours, preferably 0.5 hour to 12 hours.
The thus-obtained compound (IX), after isolation by a known method or as its reaction mixture, is used as the starting material for the next step.
When compound (I), compound (II), compound (III), compound (IX), compound (X); and each starting material compound used for the production step of compound (I) or compound (IX) are basic compounds depending on the kind of the substituent exemplified above, they may form a salt with an acid. This acid may be any as long as it does not inhibit the reaction and is exemplified by inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, sulfamic acid and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, succinic acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid and the like; acidic amino acids such as aspartic acid, glutamic acid and the like; and the like. When the obtained compound is a salt, it may be converted to a free base by a conventional method.
When compound (I), compound (II), compound (III), compound (IX), compound (X); and each starting material compound used for the production step of compound (I) or compound (IX) are acidic compounds depending on the kind of the substituent exemplified above, they may form a salt with a base. This salt with a base may be any as long as it does not inhibit the reaction and is exemplified by salt with inorganic base, salt with organic base, salt with basic amino acid and the like. Preferable examples of the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; aluminum salt, ammonium salt and the like. Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine and the like. Preferable examples of the salt with basic amino acid include salts with arginine, lysin, ornithine and the like. When the obtained compound is a salt, it may be converted to a free acid by a conventional method.
The compound (III) and compound (X) obtained by the production method of the present invention are useful as a synthetic intermediate for a pharmaceutical product such as an agent for treating diabetes as described in, for example, JP-A-9-323983 (WO97/36882) and the like, and the like. For example, the oxazole derivative described in JP-A-9-323983 can be produced using compound (III) or compound (X) as a starting material and according to the method to be mentioned below or the method described in JP-A-9-323983 or a similar method.
For example, by subjecting compound (III) or compound (X) to a halogenation reaction, a compound represented by the formula 
wherein X is a halogen atom, and other symbols are as defined above, or a salt thereof, can be produced.
The halogen atom represented by X is exemplified by fluorine, chlorine, bromine and the like.
The halogenation reaction of compound (III) is generally carried out in a solvent that does not exert an adverse influence on the reaction, in the presence of a halogenating agent. Alternatively, an excess halogenating agent may be used as a solvent.
The halogenating agent is exemplified by phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide and the like. Of these, phosphorus oxychloride is preferable.
The amount of the halogenating agent to be used is generally 1-50 equivalents), preferably 3-20 equivalents, relative to compound (III).
As the solvent that does not exert an adverse influence on the reaction, for example, halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like), ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), nitrites (e.g., acetonitrile, propionitrile and the like), esters (methyl acetate, ethyl acetate and the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene, benzotrifluoride and the like), pyridine and the like are used. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio. The solvent is preferably pyridine.
The reaction temperature is generally 20xc2x0 C. to 180xc2x0 C., preferably 50xc2x0 C.-130xc2x0 C.
The reaction time is generally 30 minutes to 20 hours.
The compound (X) is halogenated by, for example, conducting a Sandmeyer reaction known per se, namely substitution of diazo group for halogen after diazotization reaction.
The diazotization reaction is generally carried out using a diazotizing agent. As the diazotizing agent, for example, nitrites (e.g., nitrous acid, sodium nitrite and the like), alkyl nitrites (e.g., ethyl nitrite, butyl nitrite, amyl nitrite, isoamyl nitrite and the like) and the like are used. In addition, nitrosyl halide such as nitrosyl chloride and the like can be mentioned. The amount of the diazotizing agent to be used is generally about 1-10 molar equivalent(s) relative to compound (X). The diazotizing agent is preferably nitrite such as sodium nitrite and the like.
The substitution of diazo group for halogen is, for example, carried out in a solvent that does not exert an adverse influence on the reaction, in the presence of (i) copper halide, or (ii) hydrochloric acid or hydrobromic acid and copper powder or copper salt.
The copper halide to be used includes, for example, copper(I) chloride, copper(I) bromide, copper(I) iodide, copper(II) chloride, copper(II) bromide, copper(II) iodide and the like. The copper salt to be used includes, for example, copper sulfate, copper carbonate, copper oxide and the like. The amount of the copper halide, copper powder or copper salt to be used is generally about 0.001-20 molar equivalent(s) relative to compound (X).
As the solvent that does not exert an adverse influence on the reaction, for example, alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, methoxyethanol and the like), ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), acetone, dimethyl sulfoxide, phosphoric acid, acetic acid, water and the like are mentioned. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio.
The reaction temperature is generally about xe2x88x9250xc2x0 C. to 200xc2x0 C., preferably about xe2x88x9220xc2x0 C. to 150xc2x0 C.
The reaction time is generally 30 minutes to 20 hours.
The compound (XI) thus obtained can be easily isolated by a known method such as concentration, changing of liquid properties, solvent extraction, crystallization and the like. Recrystallization affords a compound having a higher purity.
In the present specification, compound (XI) wherein R3 is xe2x80x94COOR7 (R7 is as defined above) may be sometimes referred to as compound (XIa).
The compound (XVIII) useful as an agent for the prophylaxis or treatment of diabetes or diabetic complications (e.g., nephropathy, retinopathy, neuropathy and the like) can be produced by, for example, subjecting compound (XIa) to the following reaction.
The compound (XVIII), as such or after mixing with a pharmacologically acceptable carrier known per se and the like and forming into a preparation such as tablets, capsules, injections and the like, can be safely administered to a mammal (e.g., human, mouse, rat, a rabbit, dog, cat, bovine, horse, pig, monkey and the like).
While the dose of compound (XVIII) varies depending on the subject of administration, administration route and the like, for example, it is generally about 0.05-500 mg/kg body weight, preferably about 5-100 mg/kg body weight, for each oral administration to adult patients with diabetes, wherein the dose is preferably given once to 3 times a day. 
wherein R19 is an optionally substituted heterocyclic group containing nitrogen, which is bonded via a nitrogen atom, R20 is an optionally substituted hydrocarbon group, Za is a halogen atom (e.g., chlorine, bromine and the like) or xe2x80x94OSO2R10 (R10 is as defined above), and other symbols are as defined above.
With regard to the xe2x80x9coptionally substituted heterocyclic group containing nitrogen, which is bonded via a nitrogen atomxe2x80x9d represented by R19, the xe2x80x9cheterocyclic group containing nitrogen, which is bonded via a nitrogen atomxe2x80x9d is exemplified by a 5 to 10-membered aromatic heterocyclic group containing nitrogen such as 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1,2,4-triazol-1-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, tetrazol-1-yl, tetrazol-2-yl, benzimidazol-1-yl, indol-1-yl, 1H-indazol-1-yl, 1H-pyrrolo[2,3-b]pyrazin-1-yl, 1H-pyrrolo[2,3-b]pyridin-1-yl, 1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl, 1H-imidazo[4,5-b]pyrazin-1-yl and the like; a 5 to 7-membered non-aromatic heterocyclic group containing nitrogen such as 1-pyrrolidinyl, 1-piperidyl, morpholin-4-yl, thiomorpholin-4-yl, 1-piperazinyl, hexamethyleneimin-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-1-yl, imidazolin-1-yl, oxazolin-3-yl, thiazolin-3-yl, oxazin-4-yl and the like; and the like. It is preferably an aromatic heterocyclic group containing nitrogen, and particularly preferably 1-imidazolyl, 1-pyrazolyl, 1,2,4-triazol-1-yl, 1,2,4-triazol-4-yl, benzimidazol-1-yl and the like.
The above-mentioned xe2x80x9cheterocyclic group containing nitrogen, which is bonded via a nitrogen atomxe2x80x9d may have the same or different, 1 to 5, preferably 1 to 3, substituent(s) at substitutable position(s). Examples of the substituent include the substituent of the aforementioned xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d exemplified as R1. R19 is particularly preferably 1-imidazolyl group optionally substituted by 1 to 3 C1-6 alkyl group(s).
Examples of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R20 include the aforementioned xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d exemplified as R1 and the like. R20 is particularly preferably C6-14 aryl group (preferably phenyl) optionally substituted by 1 to 3 C1-6 alkyl group(s).
First, compound (XIa) and compound (XII) are reacted to give compound (XIII).
This reaction is generally carried out in a solvent that does not exert an adverse influence on the reaction, in the presence of a base.
As the base, those used for the aforementioned reaction of compound (IV) and cyanamide compound are mentioned. Alternatively, compound (XII) itself may be used as a base by using an excess compound (XII).
As the solvent that does not exert an adverse influence on the reaction, for example, ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene, benzotrifluoride and the like), N,N-dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone and the like are mentioned. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio. The solvent is particularly preferably dimethyl sulfoxide.
The amount of compound (XII) to be used is generally 1-20 equivalent(s), preferably 1-5 equivalent(s), relative to compound (XIa).
The amount of the base to be used is generally 0.01-10 equivalent(s), preferably 0.1-5 equivalent(s), relative to compound (XIa).
The reaction temperature is generally 20xc2x0 C. to 180xc2x0 C., preferably 80xc2x0 C. to 140xc2x0 C.
The reaction time is generally 15 minutes to 20 hours.
Then, compound (XIII) is subjected to reduction reaction to give compound (XIV).
This reaction is generally carried out in a solvent that does not exert an adverse influence on the reaction, in the presence of a reducing agent.
As the reducing agent, for example, metal hydrides such as alkali metal borohydride (e.g., sodium borohydride, lithium borohydride and the like) and the like; metal hydrogen complex compounds such as lithium aluminum hydride, sodium dihydro-bis(2-methoxyethoxy)aluminate and the like; organic tin compounds such as triphenyltin hydride and the like; diborane, substituted borane and the like are used. Of these, metal hydrogen complex compounds such as sodium dihydro-bis(2-methoxyethoxy)aluminate and the like are preferable.
As the solvent that does not exert an adverse influence on the reaction, for example, alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, methoxyethanol and the like), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene and the like), ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), N,N-dimethylformamide and the like are used. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio. The solvent is preferably aromatic hydrocarbons, particularly preferably toluene.
The reaction temperature is generally xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably 0xc2x0 C. to 100xc2x0 C.
The reaction time is generally 5 minutes to 10 hours.
Then, compound (XIV) is reacted with compound (XV) or halogenating agent (XVa) to give compound (XVI).
Preferable examples of compound (XV) include methanesulfonyl chloride (mesyl chloride), toluenesulfonyl chloride (tosyl chloride), benzenesulfonyl chloride and the like. Preferable examples of halogenating agent (XVa) include thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride and the like.
This reaction is generally carried out in a solvent that does not exert an adverse influence on the reaction, in the presence of a base.
As the base, for example, tertiary amines (e.g., trimethylamine, triethylamine, tributylamine, N-ethyldiisopropylamine, N-methylmorpholine and the like), aromatic amines (e.g., pyridine, picoline, quinoline, isoquinoline, N,N-dimethylaniline, N,N-diethylaniline and the like), alkali metal carbonates (e.g., sodium hydrogencarbonate, potassium carbonate, sodium carbonate, cesium carbonate and the like) and the like are used. Of these, tertiary amines such as triethylamine, N-ethyldiisopropylamine and the like are preferable.
As the solvent that does not exert an adverse influence on the reaction, for example, halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene and the like), ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), esters (methyl acetate,, ethyl acetate and the like) and the like are used. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio. The solvent is preferably aromatic hydrocarbons or ethers, particularly preferably toluene or tetrahydrofuran.
The amount of compound (XV) or halogenating agent (XVa) to be used is generally 1-5 equivalent(s) relative to compound (XIV).
The amount of the base to be used is generally 0.01-10 equivalent(s), preferably 0.1-5 equivalent(s), relative to compound (XIV).
The reaction temperature is generally xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably 0xc2x0 C. to 100xc2x0 C.
The reaction time is generally 5 minutes to 20 hours.
Furthermore, compound (XVI) and compound (XVII) are reacted to give compound (XVIII).
This reaction is generally carried out in a solvent that does not exert an adverse influence on the reaction, in the presence of a base.
As the solvent that does not exert an adverse influence on the reaction, for example, halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene, nitrobenzene and the like), ethers (e.g., ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and the like), dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like are mentioned. These solvents may be used in a combination of two or more kinds thereof at an appropriate mixing ratio. The solvent is preferably aromatic hydrocarbons or ethers, particularly preferably toluene or tetrahydrofuran.
As the base, those used for the aforementioned reaction of compound (XIa) and compound (XII) are mentioned.
The amount of each of compound (XVII) and base to be used is generally 1-10 equivalents), preferably 1-5 equivalent(s), relative to compound (XVI).
The reaction temperature is generally xe2x88x9250xc2x0 C. to 150xc2x0 C., preferably xe2x88x9210xc2x0 C. to 120xc2x0 C.
The reaction time is generally 30 minutes to 20 hours.
In this reaction, the use of a phase-transfer catalyst (PTC) is preferable for promoting the reaction. As the phase-transfer catalyst, for example, tetraethylammonium chloride, tetrabutylamimonium chloride, tetrabutylammonium bromide, benzyltriethylammonium chloride, cetylbenzyldimethylammonium chloride and the like are mentioned. Of these, tetrabutylammonium bromide is preferable.
The amount of the phase-transfer catalyst to be used is, for example, generally 0.001-5 equivalent(s) relative to compound (XVI).
The compound (XVIII) can be also produced by subjecting compound (XIV) and compound (XVII) to Mitsunobu reaction known per se.
This reaction is generally carried out in a solvent that does not exert an adverse influence on the reaction, in the presence of an organic phosphorus compound and an electrophile.
As the solvent that does not exert an adverse influence on the reaction, for example, the solvents that do not exert an adverse influence, which are used for the aforementioned reaction of compound (XVI) and compound (XVII), are mentioned.
As the organic phosphorus compound, for example, triphenylphosphine, tributylphosphine and the like are mentioned.
As the electrophile, for example, diethyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarbonyl dipiperazine and the like are mentioned.
The amount of each of the organic phosphorus compound and electrophile to be used is, for example, generally 1-5 equivalents relative to compound (XIV).
The reaction temperature is generally xe2x88x9250xc2x0 C. to 150xc2x0 C., preferably xe2x88x9210xc2x0 C. to 120xc2x0 C.
The reaction time is generally 30 minutes to 20 hours.
The aforementioned compounds (XIII), (XIV), (XVI) and (XVIII) can be easily isolated by a known method such as concentration, changing of liquid properties, solvent extraction, crystallization and the like. Recrystallization affords a compound having a higher purity. The compounds (XIII), (XIV) and (XVI) may be used for the next reaction without isolation.
Each starting material compound used for the aforementioned production step of compound (XI) and compound (XVIII) may form a salt with an acid or base in the same manner as with the aforementioned compound (I) and the like.